S116: DONOR-DERIVED CD5 CAR T CELLS FOR T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Jing Pan, Yue Tan, Biping Deng, Zhuojun Ling, Jinlong Xu, Jiajia Duan, Zelin Wang, Kai Wang, Guang Hu
Journal: HemaSphere (2023)

Background: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have a poor prognosis due to the lack of effective treatment. CAR T cells targeting CD5, which is expressed on blasts in more than 80% of T-ALL cases, might help these patients who relapse following CD7-CAR therapy or who have CD7 inexpression or low expression in tumor cells. Aims: We evaluated for the first time donor-derived CD5-targeted CAR T-cell therapy in patients with r/r T-ALL. Methods: In this phase I trial, patients with r/r T-ALL received a single infusion of CD5 CAR T cells (with CRISPR-Cas9 deletion of CD5 gene) made from either prior stem cell transplantation (SCT) donor (group A) or a matched new donors (group B). Based on the design of BOIN12, two target doses of 1×106 and 2×106 cells per kilogram (/kg) of body weight were used to explore the optimal biological dose (OBD) for each group. If manufactured cells were not sufficient, patients could be treated at a low dose of 5×105 (± 20%)/kg. The primary endpoint was safety with efficacy secondary. Patients who achieved CR post-infusion are recommended to receive SCT as consolidation. Results: Between Oct 8th, 2021 and Jan 5th, 2023, fourteen patients were enrolled, 10 patients with CD7 inexpression or low expression on blasts that are CAR-naïve (n=3) or post CD7 CAR therapy (n=7). Nine patients received prior-SCT donor-derived CD5 CAR T cells (including 5 on target dose level, 3 on low dose level and 1 on less than low dose level) and three received new donor-derived CD5 CAR T cells (3 on target dose level). This early report has approved by the Data and Safety Monitoring Committee, and indicated the OBD in each group was 1×106 (±20%)/kg. No dose-limiting toxicities (DLTs) occurred. Adverse events within 30 days included grade 3-4 cytopenias in all patients (grade 3-4 cytopenia existed in 92% prior to lymphodepletion), grade 1-2 cytokine release syndrome in 10 (83%), grade 1 neurotoxicity in 2 (17%) and grade 1 skin graft-versus-host disease (GVHD) in 8 (67%). Twelve (100%) patients achieved complete remission at day 30, and were followed up for 10.9 (range, 1.3-16.7) months by the cutoff date of Feb 28th, 2023. Three patients in group B received SCT at 30 (27-37) days, among whom two maintained remission and one died from transplant complication; nine in group A refused to SCT for economic or other personal reasons and received no further treatments, among whom two maintained remission, three relapsed with CD5 loss, and three died from late-onset grade 5 infection including two Epstein-Barr virus infections and one staphylococcus haemolyticus infection (all three contained predominantly CD5-CD7- T cells), and one died from transplant-associated thrombotic microangiopathy (TA-TMA) which may related with prior-SCT. Low level of CD7 CAR T cells were still detectable in five patients before CD5 CAR T cells infusion and disappeared (n=4) or decreased to marginal level (n=1) within two months post-infusion, and CD5 CAR T cells dominated and persisted well until last visit. Patients had a decrease in CD5+ T cells and an increase of CD5- T cells at a median count of 133 (range, 13-624)/μl at one month, which were mainly derived from CD5 gene-edited T cells in the product. Summary/Conclusion: CD5 CAR T-cell therapy is highly effective in inducing complete remission in patients with r/r T-ALL. Short-term AEs are manageable, but T-cell aplasia may result in the risk of infection at longer follow-up especially for those who had experienced CD7 CAR T therapy. Sequential SCT after CAR therapy is recommended to improve long-term outcomes.Keywords: CD5, T cell acute lymphoblastic leukemia, Acute lymphoblastic leukemia, CAR-T